Project Summary (Clinical Trial 2) Eosinophilic gastritis (EG) is an understudied rare disease characterized by eosinophil accumulation in the stomach and associated with a variety of symptoms including pain, vomiting, weight loss, and anemia. There are no US Food and Drug Administration (FDA)-approved drugs for EG or any other eosinophilic gastrointestinal disease (EGID). At present, the treatment of EG has focused upon diet elimination therapy, systemic corticosteroids, swallowed topical corticosteroids, or a combination of therapies. Though these treatments can be efficacious, there are substantial rates of non-responsiveness. Moreover, these therapies require continuous use, as a majority of patients relapse if treatment is not maintained. Dietary elimination adversely impacts personal and social aspects of life owing to the need to avoid multiple common food groups. Moreover, concerns about the long-term risks of chronic steroid use, as well as a desire to find more tolerable and/or convenient methods of treatment, have driven the search for other potential targeted therapies. In EG, there are increased levels of gastric inflammatory infiltrates, including T cells, eosinophils, and mast cells, and increased levels of chemokines and cytokines, including CCL26 (eotaxin-3), interleukin (IL)-4, IL-5, and IL-13. IL-5 is a direct eosinophil growth and activating factor, whereas IL-4 and IL-13 mediate several cardinal aspects of allergic inflammation including immunoglobulin E (IgE) production, T cell polarization to type 2 helper (Th2) cells, chemokine induction and subsequent leukocyte infiltration and activation, mucus production, barrier impairment, and end-organ dysfunction. IL-4 and IL-13 signal through a common receptor subunit, designated the IL-4Ra, that is required for signal transduction. Dupilumab is a fully human monoclonal antibody, directed against IL- 4Ra, that inhibits signaling of IL-4 and IL-13. Dupilumab has demonstrated efficacy and a favorable safety profile in adult patients with moderate-to-severe atopic dermatitis or asthma and has been recently approved for atopic dermatitis by the FDA and European Medicine Agency. The central hypothesis of this study is that dupilumab is safe and efficacious for reducing eosinophilia and a Th2 gene profile in EG. To this end, the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) will conduct a proof-of-principle, randomized, placebo-controlled trial in adults with EG. In Aim 1, we will test the primary hypothesis that dupilumab will decrease gastric eosinophil levels in patients with EG compared with placebo-treated patients. In Aim 2, we will test the hypothesis that dupilumab will reverse IL-13 signature genes expressed in the gastric mucosa of EG patients, including CDH26 and CCL26 and genes of type 2 cytokines (IL4, IL5, and IL13). It is anticipated that this study will provide proof-of-concept that EG is a type 2 allergic, immune-mediated disease and set the stage for the further development and eventual approval of a therapy for EG.